Topical formulations comprising tofacitinib

ABSTRACT

A topical formulation comprising (a) a therapeutically effective amount of tofacitinib; (b) at least one solvent; and (c) optionally one or more other pharmaceutically acceptable excipients is provided. Also provided is a method for treating and/or preventing autoimmune diseases in a subject administering said topical formulation.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention is directed to topical formulations comprisingtofacitinib. The invention is also directed to uses of said topicalformulation for the treatment of autoimmune disorders and particularly,for the treatment of vitiligo and atopic dermatitis.

DESCRIPTIONS OF THE RELATED ART

Tofacitinib,3-((3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl)-3-oxopropionitrile,has the chemical formula C₁₆H₂ON₆O and the following structural formula(I).

Tofacitinib is useful as an JAK inhibitor or an immunosuppressive agentfor organ transplants, xeno transplantation, lupus, multiple sclerosis,rheumatoid arthritis, psoriasis, psoriatic arthritis, Type I diabetesand complications from diabetes, cancer, asthma, atopic dermatitis,autoimmune thyroid disorders, ulcerative colitis, Crohn's disease,Alzheimer's disease, Leukemia and other indications whereimmunosuppression would be desirable.

Currently, tofacitinib citrate is approved in the US under the brandname XELJANZ®. XELJANZ® is an immediate release tablet form with 8 mgtofacitinib citrate (equivalent to 5 mg tofacitinib) and beingadministered twice a day XELJANZ® is also available as a once-dailytablet called XELJANZ® XR XELJANZ® XR is approved in theextended-release tablets form with 17.77 mg tofacitinib citrate(equivalent to 11 mg tofacitinib). Both XELJANZ® and XELJANZ® XR tabletsare supplied for oral administration and are indicated for the treatmentof rheumatoid arthritis.

Some adverse side effects, such as upper respiratory tract infections,headache, diarrhea, and cold symptoms, have been observed after oraladministration of tofacitinib citrate. Topical dosage forms oftofacitinib have been proposed for locally treatment and minimizingthese side effects. U.S. Pat. No. 8,541,426 discloses a topicaltofacitinib composition for treating dry eye disorders. US Pat.Application Pub. No. 20120258976 discloses a topical ointmentformulation comprising tofacitinib free base and oleyl alcohol for usein treatment of psoriasis.

However, the composition in U.S. Pat. No. 8,541,426 is a topicalformulation for ophthalmic administration, and thus its efficacy andsafety for skin application are unknown. US 20120258976 provides invitro percutaneous flux data to generate cumulative permeation and fluxprofiles after administering the topical ointment formulation, butmentions little information about the retention rate of tofacitinib inthe skin. Thus, one cannot know whether tofacitinib may provide aprolonged local treatment effect after administration. In addition,these prior art compositions are mainly used for the treatment of oculardisorders or psoriasis, and thus their treatment efficacy on other skindiseases is unclear.

Considering the limitation of the above literature, there is a need inthe art for a topical formulation of tofacitinib with a desiredretention rate as well as other physicochemical properties and adaptedto autoimmune diseases.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a topical formulationcomprising (a) a therapeutically effective amount of tofacitinib; (b) atleast one solvent; and (c) optionally, one or more otherpharmaceutically acceptable excipients.

Another object of the present invention is to provide a topicalformulation comprising (a) a therapeutically effective amount oftofacitinib citrate; (b) dimethyl sulfoxide; (c) optionally, propyleneglycol; (d) optionally, a thickening agent; (e) optionally, anantioxidant; and (f) optionally, one or more other pharmaceuticallyacceptable excipients.

Still another object of the present invention is to provide a method fortreating and/or preventing autoimmune diseases in a subject, comprisingadministering the topical formulation of the present invention to saidsubject.

The detailed technology and preferred embodiments implemented for thesubject invention are described in the following paragraphs accompanyingthe appended drawings for people skilled in this field to wellappreciate the features of the claimed invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1 is a schematic showing a flow-through diffusion cell used in thein-vitro penetration/retention study;

FIG. 2 is a statistical bar graph showing normalized partition resultsof tofacitinib in skin and receiver;

FIG. 3 is a statistical bar graph showing tofacitinib concentrations inepidermis and dermis with time course;

FIG. 4 is a statistical bar graph showing tofacitinib concentrations inthe receiver with time course;

FIG. 5 shows photographs of a male subject with facial vitiligo frombaseline, 8 weeks and 12 weeks of treatment with the tofacitinib topicalformulation of the present invention; and

FIG. 6 shows photographs of a female subject with facial vitiligo frombaseline, 8 weeks and 12 weeks of treatment with the tofacitinib topicalformulation of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The term “tofacitinib,” as used herein, refers to tofacitinib in theform of free base, pharmaceutically acceptable salts, racemates,diastereomers, isomers, analogs, and mixtures thereof.

The term “therapeutically effective amount,” as used herein, refers toan amount that alleviates or reduces one or more symptoms of a disease.

The term “degradation product,” as used herein, refers to an unwantedchemical or impurity that can develop during the manufacturing,transportation, and storage of drug products and can affect the efficacyof pharmaceutical products. It can form in response to changes in light,temperature, pH, and humidity, or due to inherent characteristics ofactive ingredients, such as their reaction with excipients or on contactwith the packaging.

In addition, unless otherwise stated herein, the terms “a (an)”, “the”or the like used in this specification and the claims shall beunderstood to encompass both the singular form and the plural form.

As described above, the present invention provides a topical formulationwith improved physicochemical properties that are beneficial for thetreatment of autoimmune diseases.

The topical formulation of the present invention comprises (a) atherapeutically effective amount of tofacitinib; (b) at least onesolvent; and (c) optionally, one or more other pharmaceuticallyacceptable excipients.

In some embodiments, the topical formulation can be formulated todifferent dosage forms, for example, a solution, a suspension, a cream,an ointment, a lotion and a gel. Preferably, the topical formulation isa solution or a gel. More preferably, the topical formulation is a gel.

In some embodiments, tofacitinib is in the form of a pharmaceuticallyacceptable salt. Such salts include, but are not limited to, citratesalt, hydrochloride salt, hydrobromide salt, oxalate salt, nitrate salt,sulfate salt, phosphate salt, fumarate salt, succinate salt, maleatesalt, besylate salt, tosylate salt, palmitate salt and tartrate salt.Preferably, the pharmaceutically acceptable salt is citrate salt.

In some embodiments, tofacitinib in the formulation is present at aconcentration from about 0.1% w/w to about 5% w/w, preferably about 1%w/w to about 4% w/w, based on the total weight of the formulation.

In some embodiments, the solvent can be, for example, dimethylsulfoxide, propylene glycol, glycerin, poly ethylene glycol, isopropylalcohol, methanol, sodium pyrrolidone carboxylate,2-hydroxypropyl-γ-cyclodextrin, acetone, purified water, ethanol,1-propanol, butanediol, 2-(2-ethoxyethoxy)ethanol (transcutol), or acombination thereof. Preferably, tofacitinib is freely soluble in thesolvent. More preferably, the solvent is dimethyl sulfoxide.

In one embodiment, the solvent is a combination of dimethyl sulfoxidewith at least one of propylene glycol, ethanol, and water.

In some embodiments, the solvent is present at a concentration fromabout 40% w/w to about 99.9% w/w, preferably about 70% w/w to about 99%w/w, more preferably about 90% w/w to about 97% w/w, based on the totalweight of the formulation.

The topical formulation of the present invention may include one or moreother pharmaceutically acceptable excipients. For example, thepharmaceutically acceptable excipients can be selected from a thickeningagent, a stabilizer, an antioxidant, a chelating agent, an oilymaterial, an emulsifier, a penetration enhancer, a pH adjusting agent, apreservative, an antimicrobial agent, an opacifier, a fragrance, acolorant, a gelling agent, a moisturizer, a surfactant, etc.

The pharmaceutically acceptable excipients used in the formulation ofthe present invention can act in more than one way. For example, athickening agent can also function as a gelling agent, a penetrationenhancer, etc., and a solvent can also function as a stabilizer (e.g.,suppressing the total degradation products of tofacitinib).

In one embodiment, the topical formulation of the present invention doesnot include oleyl alcohol.

In some embodiments, the topical formulation comprises a thickeningagent. Preferably, the thickening agent can be, for example, cellulosederivative, polyvinylpyrrolidone, carbomer polymer, carbomer derivative,maltodextrin, polydextrose, dextrates, carboxypolymethylene, polyvinylalcohol, poloxamers, polyethylene glycols, or a combination thereof.More preferably, the thickening agent is hydroxypropyl cellulose.

In some embodiments, the thickening agent is present at a concentrationfrom about 0.05% w/w to about 5% w/w, preferably about 0.1% w/w to about4% w/w, more preferably about 1% w/w to about 3% w/w, based on the totalweight of the formulation.

In some embodiments, the topical formulation comprises a gelling agent.Preferably, the gelling agent can be, for example, cellulose derivative,polyvinylpyrrolidone, carbomer polymer, carbomer derivative,maltodextrin, polydextrose, dextrates, carboxypolymethylene, polyvinylalcohol, poloxamers, polyethylene glycols, or a combination thereof.

In some embodiments, the gelling agent is present at a concentrationfrom about 0.05% w/w to about 5% w/w, preferably about 0.1% w/w to about4% w/w, more preferably about 1% w/w to about 3% w/w, based on the totalweight of the formulation.

In some embodiments, the topical formulation comprises an antioxidant.Preferably, the antioxidant can be, for example, butylatedhydroxyanisole, butylated hydroxytoluene, vitamin C, vitamin E, vitaminA, lutein, lycopene, retinyl palmitate, potassium metabisulfite, sodiummetabisulfite, sodium thiosulfate pentahydrate, 3,4-dihydroxybenzoicacid, propyl gallate, alpha-lipoic acid, ascorbyl palmitate, sodiumpyrosulfite, ubiquinone, selenium, or a combination thereof. Morepreferably, the antioxidant is butylated hydroxyanisole.

In some embodiments, the antioxidant is present at a concentration fromabout 0.05% w/w to about 5% w/w, preferably about 0.1% w/w to about 3%w/w, based on the total weight of the formulation.

In some embodiments, the topical formulation comprises a chelatingagent. Preferably, the chelating agent can be, for example,ethylenediaminetetraacetic acid (EDTA), a salt of EDTA, desferrioxamineB, deferoxamine, dithiocarb sodium, penicillamine, pentetate calcium, asodium salt of pentetic acid, succimer, trientine, nitrilotriaceticacid, trans-diaminocyclohexanetetraacetic acid (DCTA),diethylenetriaminepentaacetic acid, bis(aminoetliyl)glycolether-N,N,N′,N′-tetraacetic acid, iminodiacetic acid, citric acid,tartaric acid, fumaric acid, or a combination thereof. More preferably,the chelating agent is ethylenediaminetetraacetic acid (EDTA).

In some embodiments, the chelating agent is present at a concentrationfrom about 0.005% w/w to about 0.5% w/w, preferably about 0.01% w/w toabout 0.1% w/w, based on the total weight of the formulation.

In some embodiments, the topical formulation comprises a preservative.Preferably, the preservative can be, for example, methylparaben,propylparaben, benzyl alcohol, benzoic acid, phenol, or a combinationthereof. More preferably, the preservative is methylparaben.

In some embodiments, the preservative is present at a concentration fromabout 0.005% w/w to about 2% w/w, preferably about 0.05% w/w to about0.5% w/w, based on the total weight of the formulation.

In order to treat skin-related autoimmune disorders, it is desired todevelop a topical formulation that provides a balance of tofacitinibpenetration and retention in the skin. The therapeutic agent penetratesthrough the stratum corneum easily to reach the target site (e.g.,dermis or epidermis, where skin disorders may occur) and is retained inthe target skin layer to produce locally therapeutic effects. Thetopical formulation of the present invention achieves optimal balance ofpenetration and retention and demonstrates high retention rate in skin.

In some embodiments, when the topical formulation of the presentinvention is applied to the skin of a subject, the amount of tofacitinibretained in the skin is more than that penetrating through the skin intothe blood or systemic circulation, for 4 hours, preferably 8 hours, andmost preferably 12 hours after the application.

In one embodiment, when the topical formulation is applied to the skinof a subject, the amount of tofacitinib retained in the skin is at leastabout 4.7 times, preferably at least about 5 times, more preferably atleast about 10 times, and most preferably at least about 100 times morethan that penetrating through the skin into the blood or systemiccirculation, for 8 hours after the application.

The topical formulation of the present invention may undergo degradationto form degradation products due to its inherent characteristics orchanges in light, temperature, pH, or humidity during the manufacturing,transportation, and storage. Even a small amount of degradation productscan affect pharmaceutical safety because of the potential to causeadverse effects in patients. Therefore, it is necessary to prevent theformation of degradation products and extend the shelf life oftofacitinib products.

The topical formulation of the present invention can stabilizetofacitinib and prevent forming degradation in the formulation.

In a preferred embodiment, the total degradation products of thetofacitinib formulation are less than 2% of tofacitinib presentinitially after the formulation is stored at room temperature (i.e.,from 20° C. to 27° C.) for at least 1 month, preferably at least 3months, preferably at least 4 months, preferably at least 5 months,preferably at least 6 months, and more preferably at least 8 months.

In one embodiment, the topical formulation of the present inventioncomprises (a) a therapeutically effective amount of tofacitinib citrate;(b) dimethyl sulfoxide; (c) optionally propylene glycol; (d) optionally,a thickening agent; (e) optionally, an antioxidant; and (f) optionally,one or more other pharmaceutically acceptable excipients. In someembodiments, the topical formulation comprises (a) about 0.1% w/w toabout 5% w/w of tofacitinib citrate; (b)

about 1% w/w to about 80% w/w of dimethyl sulfoxide; (c) optionally,about 10% w/w to about 60% w/w of propylene glycol; (d) optionally,about 0.05% w/w to about 5% w/w of hydroxypropyl cellulose; (e)optionally, about 0.05% w/w to about 5% w/w of butylated hydroxyanisole;and (f) optionally, one or more other pharmaceutically acceptableexcipients, based on the total weight of the topical formulation.

In one embodiment, the topical formulation is a cream formulation. Acream is easy to spread on the skin's surface (i.e., easy to apply),less greasy compared to an ointment, easily water washable, easy to wipeaway, suitable for sensitive, dry skin and also suitable for acutelesions.

Creams are semi-solid emulsions of oily phase and water phase. They aredivided into two types: oil-in-water (O/W) form which is composed ofsmall droplets of oil dispersed in a continuous water phase, andwater-in-oil (W/O) form which is composed of small droplets of waterdispersed in a continuous oily phase. Oil-in-water creams are morecomfortable and cosmetically acceptable as they are less greasy and moreeasily washed off using water. Water-in-oil creams are more difficult tohandle but many drugs which are incorporated into creams are hydrophobicand will be released more readily from a water-in-oil cream than anoil-in-water cream. Water-in-oil creams are also more moisturizing asthey provide an oily barrier which reduces water loss from the stratumcorneum, the outermost layer of the skin. Emulsifiers are used in creamsto mix water with oils. Since water and oil do not mix but stayseparated, an emulsifier is necessary to form a homogenous mixturekeeping water and oil together.

In one embodiment, the topical cream formulation of the presentinvention comprises (a) a therapeutically effective amount oftofacitinib; (b) at least one solvent; (c) an oily material; (d) anemulsifier; and (e) optionally, one or more other pharmaceuticallyacceptable excipients. Preferably, said solvent is a combination ofdimethyl sulfoxide and water (i.e., an aqueous DMSO solution).

In some embodiments, tofacitinib in the topical cream formulation ispresent at a concentration from about 0.1% w/w to about 5% w/w,preferably about 1% w/w to about 4% w/w, based on the total weight ofthe formulation.

In some embodiments, the solvent in the topical cream formulation ispresent at a concentration from about 40% w/w to about 99% w/w,preferably about 60% w/w to about 95% w/w, more preferably about 75% w/wto about 90% w/w, based on the total weight of the formulation.

In some embodiments, the topical cream formulation comprises an oilymaterial. Preferably, the oily material can be, for example, vegetableoil, mineral oil, petrolatum, medium chain triglyceride (MCT) oil,soybean oil, sesame-seed oil, peanut oil, sunflower oil, cotton-seedoil, castor oil, olive oil, animal oils, fatty acids, synthetic oils,natural and synthetic glycerides, sterol esters, fatty alcohols,silicone oil, or a combination thereof. More preferably, the oilymaterial is mineral oil, medium chain triglyceride (MCT) oil, or castoroil. Most preferably, the oily material is castor oil.

In some embodiments, the oily material is present at a concentrationfrom about 0.05% w/w to about 60% w/w, preferably about 1% w/w to about55% w/w, more preferably about 10% w/w to about 50% w/w, based on thetotal weight of the formulation.

In some embodiments, the topical cream formulation comprises anemulsifier. Preferably, the emulsifier can be, for example, cetearylalcohol, sorbitan isostearate, glyceryl stearate, PEG-100 stearate,potassium olivate, polysorbate, sorbitan ester, decyl glucoside,hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, or acombination thereof. More preferably, the emulsifier is hydroxyethylacrylate/sodium acryloyldimethyl taurate copolymer.

In some embodiments, the emulsifier is present at a concentration fromabout 0.05% w/w to about 20% w/w, preferably about 1% w/w to about 15%w/w, based on the total weight of the formulation.

In some embodiments, the topical cream formulation of the presentinvention comprises (a) about 0.1% w/w to about 5% w/w of tofacitinib;(b) about 40% w/w to about 99% w/w of a solvent; (c) about 0.05% w/w toabout 60% w/w of an oily material; (d) about 0.05% w/w to about 20% w/wof an emulsifier; and (e) optionally one or more other pharmaceuticallyacceptable excipients. Preferably, said solvent is a combination ofdimethyl sulfoxide and water.

In some embodiments, the topical cream formulation of the presentinvention comprises (a) about 1% w/w to about 4% w/w of tofacitinib; (b)about 60% w/w to about 95% w/w of a solvent; (c) about 1% w/w to about55% w/w of an oily material; (d) about 1% w/w to about 15% w/w of anemulsifier; and (e) optionally one or more other pharmaceuticallyacceptable excipients. Preferably, said solvent is a combination ofdimethyl sulfoxide and water.

Considering that the topical formulation of the present invention hasexcellent retention rate and stability of tofacitinib, it may providemore effective treatment for skin related autoimmune diseases.Furthermore, it may also be an alternative to oral therapy for non-skinrelated autoimmune disease.

Thus, the topical formulation of the present invention can be used intreatment and/or prevention of autoimmune diseases including vitiligo,atopic dermatitis, psoriasis, epidermolysis bullosa acquista, pemphigusvulgaris, IgA-mediated bullous dermatoses, systemic lupus erythematosus,alopecia areata, porphyria, scleroderma, multiple sclerosis, rheumatoidarthritis and skin complication of Type I diabetes.

Vitiligo is a condition that causes skin depigmentation due to loss offunction and/or death of melanocytes in the epidermis, producingmilky-white patches on affected skin. The lightened lesions of the skingenerally have greater susceptibility to the damaging effects of thesun, premature aging and possibly skin cancer. Treatment options forvitiligo include medical treatments, surgical therapies, phototherapyand adjunctive treatments. Topical corticosteroid therapy has a reportedsuccess rate of up to 56%; however, long-term use of corticosteroids canresult in thinning of the skin, stretch marks, and dilation of bloodvessels.

In one embodiment, the topical formulation of the present invention isused in the treatment and/or prevention of vitiligo, as an alternativeto topical corticosteroid therapy.

Atopic dermatitis (AD) is caused by a defect of a stratum corneum, aprotective wall located in the outermost part of the skin. AD is achronic/relapsing inflammatory skin disease characterized by intensepruritus (e.g., severe itch) and by scaly and dry eczematous lesions.Steroid agents can act as an anti-inflammatory agent andimmuno-suppressant and have positive effect in treating atopicdermatitis, but if used over a long period of time, side effects such asskin-weakening, symptom of systemic hormone, and toxicity can occur.

In one embodiment, the topical formulation of the present invention isused in the treatment and/or prevention of atopic dermatitis, as analternative to steroid therapy.

In some embodiments, the topical formulation is a once or twice-dailyformulation. That is, the formulation is applied to the skin of asubject once a day or twice a day.

In some embodiments, tofacitinib is the sole active ingredient in theformulation. These embodiments may include ingredients that could beused as active ingredients in prior art formulations, as long as theamounts of these ingredients in the provided formulations are atsub-therapeutic levels for the purposes of the provided formulations inthe instant application. The invention also provides embodiments whereintofacitinib is not the only active ingredient and can be combined withother active ingredients.

In some embodiments, tofacitinib is administered to the skin at a dailytherapeutically effective dose of about 0.5 mg/cm² to about 60 mg/cm².

The present invention also provides a method for treating and/orpreventing autoimmune diseases in a subject, comprising administeringthe topical formulation of the present invention to the subject.

Preferably, the autoimmune disease is vitiligo or atopic dermatitis.

Hereinafter, the present invention will be further illustrated withreference to the following examples. However, these examples are onlyprovided for illustrative purposes, but not to limit the scope of thepresent invention in any way.

Example 1 Solubility of Tofacitinib Citrate

A solubility study was conducted in the course of formulationdevelopment. Excess of tofacitinib citrate was added to various solventlisted in Table 1. The suspension was stirred overnight and filteredthrough 0.22 μm filter. The filtrate was diluted into suitableconcentration. The concentration of tofacitinib citrate in each solventwas determined by HPLC method. The solubility results of tofacitinibcitrate in various solvents are summarized in Table 1.

TABLE 1 Solubility of Tofacitinib Citrate Solubility Descriptive APISolvent (mg/mL) Term Tofacitinib Dimethyl sulfoxide >100 Freely solubleCitrate (DMSO) Ethanol 0.48 Very slightly soluble Propylene Glycol (PG)1.92 Slightly soluble H₂O 3.00 Slightly soluble 0.1N HCl 23.86 Sparinglysoluble pH 3.0, 50 mM 0.60 Very slightly soluble Citrate Buffer pH 4.5,50 mM 1.81 Slightly soluble Acetate Buffer pH 4.5, 50 mM Acetate 3.16Slightly soluble Buffer/PEG300 = 70/30 pH 7.5, 50 mM 0.12 Very slightlysoluble Phosphate Buffer pH 7.5, 50 mM Phosphate 1.59 Slightly solubleBuffer/PEG300 = 70/30 pH 6.8, 50 mM 0.12 Very slightly soluble PhosphateBuffer pH 9.0, 50 mM 0.12 Very slightly soluble Phosphate Buffer

The results showed that tofacitinib citrate is freely soluble indimethyl sulfoxide (DMSO), slightly soluble in water and propyleneglycol (PG), and very slightly soluble in ethanol. To prepare thedesired concentration of tofacitinib topical formulation (32 mg/mL),DMSO was chosen as a solvent. It also showed that the solubility oftofacitinib citrate is pH-dependent. The aqueous solubility oftofacitinib citrate decreases as pH increases from 1 to 3, slightlyincreases at pH 4.5 and remains relatively low above pH 6.8.

Example 2 Compatibility Study of Tofacitinib Citrate

At the early stage of formulation development, to understand thepotential incompatibilities between tofacitinib citrate and excipients,several compatibility tests were performed. Specifically, vials withrubber stoppers containing the mixtures of dissolved tofacitinib citratewith excipients, as specified in Table 2 below, were incubated in achamber under the condition of 60° C. for seven days. The totaldegradation products in the mixtures were further analyzed by HPLC.

TABLE 2 Compatibility Study of Tofacitinib Citrate Total The Mixtures ofDissolved Tofacitinib Degradation Citrate with Excipients 60° C., 1 WeekProducts (%) Tofacitinib Citrate 0.06 Tofacitinib Citrate/DMSO 4.17Tofacitinib Citrate/propylene glycol/DMSO 0.47 TofacitinibCitrate/isopropyl alcohol (IPA)/DMSO 0.51 Tofacitinib Citrate/polyethylene glycol 5.23 400 (PEG400)/DMSO Tofacitinib Citrate/Glycerin/DMSO3.67 Tofacitinib Citrate/methanol/DMSO 2.06 Tofacitinib Citrate/0.5NNaOH/DMSO 2.19 Tofacitinib Citrate/hydroxypropyl cellulose (HPC)/DMSO4.96 Tofacitinib Citrate/ethanol/DMSO 1.01

The compatibility study results are shown in Table 2. Althoughtofacitinib citrate exhibits good solubility in DMSO, the compatibilityof tofacitinib citrate in DMSO might be a concern. It was observed thatDMSO induced degradation of tofacitinib citrate, resulting in totaldegradation products of 4.17%. Surprisingly, the compatibility issue wasresolved by adding propylene glycol, ethanol or isopropyl alcohol (IPA).It was found that in the presence of propylene glycol, ethanol orisopropyl alcohol, the total degradation products of tofacitinib citratein DMSO were significantly suppressed. Therefore, a combination of DMSOwith other solvents/excipients like PG, ethanol or IPA can be used inthe formulation to dissolve tofacitinib citrate and at the same timereduce the total degradation products of tofacitinib citrate in DMSO.

Example 3 Preparation of Tofacitinib Topical Formulations

Based on the compatibility study result, a preliminary formulation oftofacitinib citrate was designed as follows (Table 3). DMSO, or acombination of DMSO with PG, ethanol, and/or water, was utilized as asolvent to dissolve the active ingredient tofacitinib citrate. Alltofacitinib citrate should be fully dissolved as a clear solution. Theformulation can utilize one or more pharmaceutically acceptableexcipients to modify its characteristics or change its dosage form.Herein, sodium hydroxide was utilized as a pH adjusting agent. Thequantity sufficient (q.s.) of 0.5N sodium hydroxide solution wasproperly added to reach the desired pH. Butylated hydroxyanisole wasutilized as an antioxidant to inhibit the oxidation of the formulation.Hydroxypropyl cellulose was utilized as a thickening agent to controlthe rheological properties to formulate a solution or gel form. Oilphase and water phase are key components of semi-solid dosage forms.They are divided into two types: oil-in-water (O/W) form which iscomposed of small droplets of oil dispersed in a continuous water phase,and water-in-oil (W/O) form which is composed of small droplets of waterdispersed in a continuous oily phase. Emulsifiers are compounds thattypically have a polar or hydrophilic (i.e. water-soluble) part and anon-polar (i.e. hydrophobic or lipophilic) part. An emulsifier is asubstance that stabilizes an emulsion by increasing its kineticstability.

TABLE 3 Ingredients of Tofacitinib Topical Formulations IngredientFunction Tofacitinib citrate Active ingredient DMSO Solvent PropyleneGlycol Solvent Ethanol Solvent 0.5N NaOH pH adjusting agentHydroxypropyl Cellulose Thickening agent Butylated Hydroxyani soleAntioxidant Castor Oil Oily material (oil phase) Water Waterphase/Solvent Hydroxyethyl acrylate/sodium acryloyldimethyl Emulsifiertaurate copolymer

Table 4 shows twenty DMSO based tofacitinib topical formulations (P1 toP20) and an ointment formulation (C1) as a comparative example. C1ointment is disclosed in US 20120258976, which contains free base oftofacitinib.

TABLE 4 Tofacitinib Topical Formulations Tofacitinib Topical (% W/W)Formulations P1 P2 P3 P4 P5 P6 P7 P8 Tofacitinib Free Citrate saltBase/Citrate salt 3.2 3.2 3.2 3.2 3.2 3.2 1.0 3.2 DMSO 45.5 45.5 45.545.5 45.5 45.5 45.5 45.5 Propylene Glycol 11 11 40 37.5 37.5 37.5 13.237.4 Hydroxypropyl Cellulose 2.5 2.5 — 2.5 2.5 4 2.5 2.5 Carbomer type C— — — — — — — — Purified water 11.3 — 11.3 11.3 — 9.8 11.3 — EthylAlcohol 95% 26.5 26.5 — — — — 26.5 — 0.5 N NaOH — 11.3 — — 11.3 — — 11.3Butylated Hydroxyanisole — — — — — — — 0.1 Oleyl Alcohol — — — — — — — —Glycerin — — — — — — — — PEG 400 — — — — — — — — PEG 3350 — — — — — — —— Total 100 100 100 100 100 100 100 100 Tofacitinib Topical (% W/W)Formulations P9 P10 P11 C1 Tofacitinib Free Free base Base/Citrate salt2.0 2.0 2.0 2.0 DMSO 45.5 45.5 45.5 — Propylene Glycol 37.5 38.6 38.918.0 Hydroxypropyl Cellulose 2.5 4 — — Carbomer type C — — 1.0 Purifiedwater 12.5 9.9 qs — Ethyl Alcohol 95% — — — — 0.5 N NaOH — — adjust topH 5-6 — Butylated Hydroxyanisole — 0.1 0.1 0.1 Oleyl Alcohol — — — 2.0Glycerin — — — 17.9 PEG 400 — — — 30.0 PEG 3350 — — — 30.0 Total 100 100100 100 Tofacitinib Topical (% W/W) Formulations P12 P13 P14 P15 P16Tofacitinib Free Free base Citrate salt Free base Base/Citrate salt 2.02.0 2.0 3.2 2.0 DMSO 45.5 45.5 45.5 45.5 10 Propylene Glycol — 5 — 39 50Hydroxypropyl Cellulose — — — — 2.5 Carbomer type C — — — 1 — Purifiedwater 22.4 6.4 22.4 — 35.4 Ethyl Alcohol 95% — — — — — 0.5 N NaOH — — —11.3 — Butylated Hydroxyanisole 0.1 0.1 0.1 — 0.1 ButylatedHydroxytoluene Tween 60 5 — 5 — — Span 60 5 — 5 — — Mineral Oil 10 — 20— — Caster Oil White Petrolatum 5 40 — — — Glyceryl monostearate 5 — — —— Sodium lauryl sulfate — 1 — — — Edetate Disodium, 2H₂O Methylparabenhydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer Total100 100 100 100 100 Tofacitinib Topical (% W/W) Formulations P17 P18 P19P20 Tofacitinib Free Citrate Salt Base/Citrate salt 3.2 3.2 3.2 3.2 DMSO42.5 42.5 42.5 20 Propylene Glycol 40.1 39.82 39.87 10 HydroxypropylCellulose 2.5 2.5 2.5 — Carbonier type C — — — — Purified water — — —51.6 Ethyl Alcohol 95% — — — — 0.5 N NaOH 11.0 11.3 11.3 — ButylatedHydroxyanisole 0.45 0.45 0.45 1.0 Butylated Hydroxytoluene 0.18 0.180.18 0.2 Tween 60 — — — — Span 60 — — — — Mineral Oil — — — — Caster Oil10 White Petrolatum — — — — Glyceryl monostearate — — — — Sodium laurylsulfate — — — — Edetate Disodium, 2H₂O 0.01 — — — Methylparaben 0.050.05 — — hydroxyethyl acrylate/sodium 4 acryloyldimethyl tauratecopolymer Total 100 100 100 100

The DMSO based formulations were prepared by the following steps:

1. Prepare API/DMSO Solution: dissolve the active agent (tofacitinibfree base or citrate salt) in DMSO;

2. Prepare Thickening/Gelling Solution: dissolve a thickening agent orgelling agent in a solvent (e.g., propylene glycol and/or ethanol) ifnecessary,

3. Prepare Chelating Solution: dissolve a chelating agent in a sodiumhydroxide solution if necessary;

4. Prepare API/DMSO Mixing Solution: add an antioxidant, the chelatingsolution, a preservative, an oily material, an emulsifier, or otherpharmaceutically acceptable excipients into the API/DMSO solution ifnecessary;

5. Add the API/DMSO Mixing solution into water if necessary; and

6. Add the API/DMSO Mixing solution into the Thickening/Gelling Solutionif necessary; and

7. Keep stirring until all the compositions were homogenous.

Example 4 Stability Study of Tofacitinib Topical Formulations

The nine formulations (P1 to P6, P8, P9 and C1) were subjected to thestability study at 25° C./60% relative humidity (RH) and 40° C./75%relative humidity for at least 1 month. The one month stability resultof the nine formulations was summarized in Table 5. The physical andchemical stability was also evaluated. Stability data of the formulation(P8) for an extended period were collected in Table 6.

TABLE 5 Stability of Nine Formulations Formulation P1 P2 P3 P4 P5Tofacitinib citrate form Initial pH 5.16 6.28 4.70 4.76 5.88 Totaldegradation products (% w/w) Initial 0.03 0.03 0.04 0.06 0.13 25° C./60%0.06 0.07 0.12 0.21 0.12 RH, 1 Month 40° C./75% 0.29 0.80 1.17 1.29 0.17RH, 1 Month Increased 0.26 0.77 1.13 1.23 0.04 after 40° C./ 75% RH, 1Month Physical crystalline crystalline freely Non- Non- propertyprecipitate precipitate runny runny runny Preferred Preferred candidatecandidate Formulation P6 P8 P9 C1 Tofacitinib citrate Free base formInitial pH 4.77 N/A 6.05 N/A Total degradation products (% w/w) Initial0.04 0.08 0.82 2.65 25° C./60% 0.19 0.08 1.19 4.03 RH, 1 Month 40°C./75% 1.01 0.35 1.25 6.14 RH, 1 Month Increased 0.97 0.27 0.43 3.49after 40° C./ 75% RH, 1 Month Physical crystalline Non- Non- poorproperty precipitate runny runny stability Preferred Preferred candidatecandidate

TABLE 6 Stability Data of the Total degradation Formulation P8 for anExtended Period products (% w/w) 25° C./60% RH Initial 0.08 3 Months0.08 4 Months 0.08 5 Months 0.09 6 Months 0.48 8 Months 0.77 40° C./75%RH Initial 0.08 1 Month  0.35

C1 ointment formulation shows poor stability, and the weight percentageof total degradation products is 6.14%. The other formulations, P1-P6,P8 and P9, show better stability when compared to C1 ointmentformulation. In sum, the DMSO based formulations (P1 to P6, P8 and P9)exhibit higher stability than the ointment formulation (C1), whethertofacitinib is in the form of free base or citrate salt. Moreover, thestability result of the formulation P8 reveals great stability at morethan 1 month. The weight percentage of total degradation products ismerely 0.77% at 25° C./60% relative humidity (RH) for 8 months.

However, crystalline precipitate was observed in P1, P2 and P6. P3 isless preferred due to its freely runny property. It is inconvenient toapply on a lesion site when formulations tend to flow freely. Therefore,P4, P5, P8 and P9 are preferred formulation candidates.

Example 5 In-Vitro Penetration/Retention Study of Tofacitinib TopicalFormulations

A number of formulations containing tofacitinib free base or citratesalt were subjected to in-vitro penetration/retention study. Generally,both hairless guinea pig and pig are well-established models forpredicting human skin absorption. By contrast, other models usinglaboratory animals such as rat, rabbit, and guinea pig with hair oftenresult in overrating the human skin absorption. Flank skin obtained fromseven months-old pig (Landrace pig and Duroc pig crossbreed) in TaiwanLivestock Company was used as a penetration membrane. Vertical diffusioncell (USP/NF<725>, FIG. 1) was applied for the penetration/retentiontest. Specifically, hair on the skin was clipped before dermatoming to athickness of 750 Electrical resistance of the skin was confirmed toensure the skin integrity. The skin was placed on the top of diffusioncell in contact with receptor phase, which was filled with phosphatebuffered saline (PBS) (pH 7.4) with 20% polyethylene glycol 300 (PEG300) (at 37° C.). Approximately 280 mg of tofacitinib formulations wereadded onto the skin surface in the donor compartment. After 8 hours, theresidual formulation on the skin surface was removed and skin surfacewas again cleaned carefully. Stratum corneum was removed and the skinwas weighed and minced, and extracted with acetonitrile/methanol/waterextraction solution by vigorous shaking for 1 hour. The skin extractswere centrifuged and analyzed by high performance liquid chromatography(HPLC).

The relative tofacitinib amounts of skin extract (μg)/receiver (μg) areshown in TABLE 7. The data shows that P1 to P6 and P9 are all higherthan C1. It indicates that P1 to P6 and P9 DMSO based formulations tendto keep tofacitinib in the skin more than to penetrate across the skin.

TABLE 7 The Relative Amount of Skin Extract/Receiver of P1 to P6, P9 andC1 Skin extract/Receiver Formulation (range) P1 13.8 (9.8-17.4) P2 32.7(24.8-40.8) P3 101.0 (11.9-246.4) P4 125.6 (77.9-235.2) P5 128.2(72.3-242.5) P6 138.7 (70.8-199.5) P9 31.2 (9.8-59.6) C1 4.7 (2.5-6.4)

FIG. 2 shows the partition in skin and the receiver after 8 hourstreatment. Comparing the DMSO based formulations (P1 to P6 and P9) withC1, the results showed that tofacitinib ointment (C1) had the highestpartition in the receiver and the lowest in skin, indicating that thisformulation facilitates tofacitinib penetrating across skin into theblood or systemic circulation more than that retaining in skin among allthe formulations. This result suggests that the DMSO based formulationsnot only improve the stability of the product, but also increase theamounts of tofacitinib retained in the skin.

Formulations P1 and P2 have the highest partitions in the receiver amongall the DMSO based formulations. This might be attributable to ethylalcohol in the formulation that enhances the penetration of tofacitinibinto the receiver and reduces the portion in skin accordingly.Therefore, DMSO based formulations without ethyl alcohol are morepreferred than those added with ethyl alcohol.

Comparing P4 (without 0.5N NaOH) and P5 (with 0.5N NaOH), adding sodiumhydroxide to change the pH of the formulation did not make significantdifference for the penetration/retention of tofacitinib. In sum, theformulations P4, P5 and P6 exhibit highest amounts of tofacitinibretained in the skin than that penetrating through the skin into theblood or systemic circulation.

Example 6 More Excipient Effects on the Partition of Tofacitinib inEpidermis, Dermis, and the Receiver

An individual study was performed to see the effect of the antioxidantagent, butylated hydroxyanisole (BHA), on the partition of tofacitinibin epidermis, dermis, and the receiver. Four months-old pig (Landracepig and Duroc pig crossbreed) flank skin obtained from PigModel AnimalTechnology Co., Ltd. was used in in-vitro penetration/retention study.Formulation P8 is a modified formulation by adding 0.1% BHA incomparison to P5 formulation (Table 4). Approximately 280 mg of P5 or P8were added onto the skin surface in the donor compartment. After 8hours, the residual formulation on the skin surface was removed andcleaned carefully. Stratum corneum was removed and the skin was thenheat-separated into epidermis and dermis. The separated epidermis anddermis were weighed and extracted. Together with receiver samples, bothepidermis and dermis extracts were submitted to HPLC analyses for theconcentrations of tofacitinib citrate. Results are shown in below Table8.

The results showed that BHA didn't make significant difference in theskin extracts and receivers, indicating that the antioxidant BHA was notcritical to the partition of tofacitinib in the skin.

TABLE 8 Levels of Tofacitinib Citrate in Epidermis, Dermis and Receiversafter 8-hr Application of Topical Formulations P5 and P8 EpidermisDermis Receiver Formulation (μg/g) (μg/g) (ng/cm²) P5 176.45 ± 122.93 7.58 ± 4.70 66.29 ± 40.12 P8 292.93 ± 104.41 13.22 ± 8.67 21.06 ± 17.23

Example 7 The Ratio of Solvent/Tofacitinib Effect on the Partition ofTofacitinib in Epidermis, Dermis, and the Receiver with Time Course

An in-vitro penetration/retention study was conducted to compare thecumulative amounts of tofacitinib retained in the skin and entering intoreceivers with time course. This experiment aims to investigate theeffect of the ratio of solvent/tofacitinib on the penetration/retention,so as to ensure that DMSO based formulations have a preference oftofacitinib retention in skin across all the time course up to 12 hours.

Formulations P5 and P7 were shown in Table 4, P7 has a higherDMSO/tofacitinib ratio comparing with P5's. Approximately 280 mg oftofacitinib formulations were added onto the skin surface (1 cm²) in thedonor compartment. The dermal side of each skin section was in contactwith receiver medium. A uniform, 37° C. temperature was achieved withinthe receiver chamber by circulating water through the cell jacket. After4, 8, and 12 hours from the administration, receiver solutions werecollected and epidermis and dermis were separated and extracted.Tofacitinib concentrations in skin extracts and receiver solutions wereanalyzed by HPLC.

As shown in FIGS. 3 and 4, P5 and P7 had comparable tofacitinib levelsin epidermis and dermis as well as in the receiver solutions at thethree time points, indicating that a higher DMSO/API ratio could achievesimilar penetration/retention effect.

According to the above studies, the topical tofacitinib formulation ofthe present invention tends to be retained in the skin and hasrelatively low concentrations in the receivers during the period up to12 hours after administration. Therefore, the formulation of the presentinvention may have lower systemic exposure of tofacitinib and thus canreduce the systemic side effects as compared with oral dosage forms andC1 ointment.

Example 8 Clinical Trials of Tofacitinib Topical Formulations in theTreatment of Atopic Dermatitis

A randomized, double-blinded, placebo-controlled study was designed and6 evaluable patients received either placebo or the tofacitinib topicalformulations of the present invention at ratio of 1:2. The purpose ofthis study is to evaluate the efficacy of the tofacitinib topicalformulations of the present invention twice daily (BID) in patients withatopic dermatitis compared to placebo (vehicle). Either tofacitinibtopical formulations or placebo were applied over the targeted skincorresponding to 16 to 100 cm² area twice daily (BID) for 8 consecutiveweeks.

The Atopic Dermatitis Severity Index (ADSI) was used to assess theseverity of the dermatitis. This index (range, 0-15) consists of the sumof the scores for pruritus, erythema, exudation, excoriation, andlichenification, all scored on a 4-point (range, 0-3) scale. At Week 0(baseline), 2, 4, and 8, ADSI were scored. Efficacy endpoints includedtotal clearance (ADSI=0), partial clearance (0<ADSI≤2) and ≥4-pointimprovement from Week 0 (baseline) (Baseline minus Visit score) in ADSIat Week 2, 4, and 8.

Table 8 shows the clinical study result of ADSI at Week 0, 2, 4 and 8.Compare Week 2 and Week 0 (baseline), the sum score of ADSI in allsubjects receiving the tofacitinib topical formulations of the presentinvention significantly decrease. And they achieved the efficacyendpoint that ADSI is clearance (ADSI=0) or partial clearance (0<ADSI≤2)at Week 8. The Average ADSI score and ADSI score improvement werecalculated in Table 9. The Average ADSI score improvement of thesubjects receiving tofacitinib topical formulations of the presentinvention dramatically increase to 3.75 at Week 2. Then it slightlyincreases to 4.75 at Week 4 and eventually to 5 at Week 8. Compare tothe subjects with tofacitinib, the subjects with placebo exhibits only1.5 at Week 2, then down to 1 at Week 4 and eventually increase to 3.5at week 8.

According to the above studies, the conditions of atopic dermatitis ofthe subjects receiving the tofacitinib topical formulations of thepresent invention were dramatically improved in 2 weeks and the efficacywas achieved in 8 weeks. Therefore, the subjects who received thetofacitinib topical formulations of the present invention exhibited muchbetter improvement for at least 8 weeks than the subjects receivingplacebo.

TABLE 8 Clinical study result of ADSI at Week 2, 4 and 8 receivedsubjects ADSI score Week 0 Week 2 Week 4 Week 8 Placebo R1 Erythema 2 22 2 Pruritus 2 2 3 1 Exudtion 1 1 1 0 Excoriation 1 1 1 0Lichenification 1 1 2 1 SUM 7 7 9 4 R2 Erythema 1 1 0 0 Pruritus 2 0 0 0Exudtion 0 0 0 0 Excoriation 1 0 0 0 Lichenification 1 1 1 1 SUM 5 2 1 1Tofacitinib R3 Erythema 2 1 1 1 Pruritus 1 0 0 0 Exudtion 1 0 0 0Excoriation 2 1 0 1 Lichenification 1 0 0 0 SUM 7 2 1 2 R4 Erythema 2 10 1 Pruritus 2 1 0 0 Exudtion 0 0 0 0 Excoriation 1 1 0 1Lichenification 2 0 1 0 SUM 7 3 1 2 R5 Erythema 2 1 0 0 Pruritus 1 1 1 1Exudtion 1 0 1 0 Excoriation 2 1 1 0 Lichenification 2 2 2 1 SUM 8 5 5 2R6 Erythema 2 0 0 0 Pruritus 1 1 0 0 Exudtion 1 0 0 0 Excoriation 0 0 00 Lichenification 0 0 0 0 SUM 4 1 0 0

TABLE 9 Average ADSI score and ADSI score Improvement at Week 2, 4 and 8Average ADSI score range, 0-15) Week 0 Week 2 Week 4 Week 8 Placebo (n =2) 6 4.5 5 2.5 Tofacitinib (n = 4) 6.5 2.75 1.75 1.5 Average ADSI scoreImprovement Placebo (n = 2) 0 1.5 1 3.5 Tofacitinib (n = 4) 0 3.75 4.755

Example 9 Clinical Trials of Tofacitinib Topical Formulations in theTreatment of Vitiligo

A randomized, double-blind, placebo-controlled, within-subjectcontrolled, proof-of-concept study was carried out to characterize theefficacy of the tofacitinib topical formulations of the presentinvention topically administered BID (twice daily) for up to 12 weeks insubjects with vitiligo.

A total of 10 subjects were enrolled and randomized. Each targetdepigmentation areas localized to the face/neck/arms/legs/trunk ofeligible subjects received either the tofacitinib topical formulation orplacebo. Treatments were applied topically BID for up to 12 weeks at anapplication coverage of approximately 3 mg/cm². All patients wereevaluated at baseline and monthly intervals for clinical improvement(repigmentation level) and photographs.

FIG. 5 shows photographs of a male subject with facial vitiligo frombaseline, 8 weeks and 12 weeks of treatment with the tofacitinib topicalformulation of the present invention. A significant repigmentation ofthe forehead (percent improvement≅30%) and chin (percent improvement60%) was observed from baseline through 12 weeks.

FIG. 6 shows photographs of a female subject with facial vitiligo frombaseline, 8 weeks and 12 weeks of treatment with the tofacitinib topicalformulation of the present invention. A significant repigmentation ofthe forehead (percent improvement≅90%) was nearly completed frombaseline through 12 weeks.

The above disclosure is related to the detailed technical contents andinventive features thereof. People skilled in this field may proceedwith a variety of modifications and replacements based on thedisclosures and suggestions of the invention as described withoutdeparting from the characteristics thereof.

What is claimed is:
 1. A method for treating an autoimmune disease in asubject, comprising administering a topical formulation to said subject,wherein the topical formulation comprises: (a) a therapeuticallyeffective amount of tofacitinib; (b) at least one solvent comprisingdimethyl sulfoxide (DMSO) and propylene glycol; and (c) optionally, oneor more other pharmaceutically acceptable excipients.
 2. The method ofclaim 1, wherein said autoimmune disease is selected from vitiligo,atopic dermatitis, psoriasis, epidermolysis bullosa acquista, pemphigusvulgaris, IgA-mediated bullous dermatoses, systemic lupus erythematosus,alopecia areata, porphyria, scleroderma, rheumatoid arthritis, multiplesclerosis and skin complication of Type I diabetes.
 3. The method ofclaim 1, wherein tofacitinib is administered to the skin at a dailytherapeutically effective dose of about 0.5 mg/cm² to about 60 mg/cm².4. The method of claim 1, wherein the topical formulation is in the formselected from the group consisting of a solution, a suspension, a cream,an ointment, a lotion and a gel.
 5. The method of claim 1, wherein thetopical formulation is in the form selected from a solution and a gel.6. The method of claim 1, wherein said tofacitinib is in the form of apharmaceutically acceptable salt selected from citrate salt,hydrochloride salt, hydrobromide salt, oxalate salt, nitrate salt,sulfate salt, phosphate salt, fumarate salt, succinate salt, maleatesalt, besylate salt, tosylate salt, palmitate salt and tartrate salt. 7.The method of claim 6, wherein said pharmaceutically acceptable salt iscitrate salt.
 8. The method of claim 1, wherein said solvent furthercomprises at least one of propylene glycol, ethanol, and water.
 9. Themethod of claim 1, wherein said pharmaceutically acceptable excipient isselected from the group consisting of a thickening agent, a stabilizer,an antioxidant, a chelating agent, an oily material, an emulsifier, apenetration enhancer, a pH adjusting agent, a preservative, anantimicrobial agent, an opacifier, a fragrance, a colorant, a gellingagent, a moisturizer, a surfactant, and a combination thereof.
 10. Themethod of claim 1, wherein said pharmaceutically acceptable excipient isa thickening agent.
 11. The method of claim 10, wherein said thickeningagent is selected from the group consisting of a cellulose derivative,polyvinylpyrrolidone, a carbomer polymer, carbomer derivative,maltodextrin, polydextrose, dextrates, carboxypolymethylene, polyvinylalcohol, poloxamers, polyethylene glycols and mixtures thereof.
 12. Themethod of claim 1, wherein when the formulation is applied to the skinof a subject, the amount of tofacitinib retained in the skin is morethan that penetrating through the skin into the blood or systemiccirculation, for 4 hours after the application.
 13. The method of claim1, wherein when the formulation is applied to the skin of a subject, theamount of tofacitinib retained in the skin is at least about 4.7 timesmore than that penetrating through the skin into the blood or systemiccirculation, for 8 hours after the application.
 14. The method of claim1, wherein less than 2% of total degradation products are observed afterstored at room temperature for at least 1 month.
 15. A method fortreating an autoimmune disease in a subject, comprising administeringthe topical formulation to said subject, wherein the topical formulationcomprises: (a) a therapeutically effective amount of tofacitinibcitrate; (b) dimethyl sulfoxide; (c) propylene glycol; (d) optionally, athickening agent; (e) optionally, an antioxidant; and (f) optionally,one or more other pharmaceutically acceptable excipients.
 16. The methodof claim 15, comprising: (a) about 0.1% w/w to about 5% w/w oftofacitinib citrate; (b) about 1% w/w to about 80% w/w of dimethylsulfoxide; (c) about 10% w/w to about 60% w/w of propylene glycol; (d)optionally, about 0.05% w/w to about 5% w/w of hydroxypropyl cellulose;(e) optionally, about 0.05% w/w to about 5% w/w of butylatedhydroxyanisole; and (f) optionally, one or more other pharmaceuticallyacceptable excipients, based on the total weight of the topicalformulation.